Morpholino derivatives of daunorubicin and doxorubicin

ABSTRACT

Anthracycline glycosides of the general formula (A):    &lt;IMAGE&gt;  (A) wherein X is hydrogen or hydroxy and R is hydrogen or a methyl or a hydroxymethyl group; and their pharmaceutically acceptable salts; are useful as antitumor agents.

The present invention relates to anthracycline antitumor glycosides,methods for their preparation, compositions containing them and the useof the compounds.

Daunorubicin (daunomycin) and doxorubicin (adriamycin) are bothwell-known anthracycline antitumor glycosides, and both theirpreparation and use are amply described in the prior art. Daunomycinone,the aglycone of daunorubicin, which is one of the starting material usedin the preparation of the compounds of the invention is also a wellknown material and is described and claimed in British Pat. No.1,003,383.

The present invention provides, in one aspect thereof, a new class ofanthracycline glycoside antibiotics of the formula (A): ##STR2## whereinX is hydrogen or hydroxy and R is hydrogen or a methyl or hydroxymethylgroup and pharmaceutically acceptable salts thereof such as thehydrochloride. More particularly the new anthracycline glycosides are:

I: 3'-deamino-3'-(2"-methoxy-4"-morpholinyl)daunorubicin (X=R=H)

II: 3'-deamino-3'-(2"-methoxy-4"-morpholinyl)doxorubicin (R=H; X=OH)

III: 3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)daunorubicin(R=CH₃ ; X=H)

IV: 3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)doxorubicin(R=CH₃ ; X=OH)

V:3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)daunorubicin(R=CH₂ OH; X=H)

VI:3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)doxorubicin(R=CH₂ OH; X=OH)

The compounds of formula (A) are prepared by the formation of asubstituted morpholinyl ring at C-3' on the sugar moiety of theanthracyclines daunorubicin and doxorubicin through a reductivealkylation, based on using a chiral dialdehyde of the general formula(B), wherein R represents a hydrogen atom or a methyl or a hydroxymethylgroup. ##STR3## Accordingly, the present invention provides a processfor the preparation of an anthracycline glycoside of formula (A) asdefined in claim 1 or a pharmaceutically acceptable salt thereof, whichprocess comprises reacting daunorubicin or doxorubicin or an acidaddition salt thereof with an excess of an aldehyde of formula (B) inthe presence of an alkali metal cyanoborohydride and, if desired,converting a compound of formula (A) thus obtained into apharmaceutically acceptable salt thereof.

The reductive alkylation is typically carried out using an excess of thedialdehyde in a mixed aqueous polar organic medium, such aswater-acetonitrile, generally at a pH of about 7 in presence of analkali metal cyanoborohydride e.g. sodium or potassium cyanoborohydride.The reaction can be usually completed in two hours at room temperature.The desired product is isolated from the reaction mixture by solventextraction and purified by column chromatography.

For example, to obtain a hydrochloride of the invention daunorubicin ordoxorubicin, in the form of its hydrochloride, is dissolved in a mixtureof acetonitrile-water (1:1 v/v) and, after having adjusted the pH to 7.4with an aqueous solution of sodium hydrogen carbonate, is reacted atroom temperature with an excess (7-10 equiv.) of a dialdehyde of formula(B): ##STR4## wherein R represents a hydrogen atom or a methyl or ahydroxymethyl group, in the presence of an aqueous solution of NaBH₃ CNin an equivalent amount with respect to the starting daunorubicin toobtain, after a 15 minutes stirring at room temperature, the rawglycoside compound of formula (A) (X=H or OH) which, after purificationby flash chromatography on silica gel column using as eluting systemmethylene dichloride-acetone (96:5 v/v) is isolated as itshydrochloride.

A dialdehyde of formula (B) is prepared via a Malaprade reaction on themethyl glycoside of a sugar in pyranic form. More particularly, this isachieved by periodic acid oxidation of the methylglycoside of:

(i) arabinose in pyranic form to afford the dialdehyde (BI) (R=H)

(ii) rhamnose affords (BII) (R=Me)

(iii) glucose affords (BIII) (R=CH₂ OH)

Moreover the invention provides pharmaceutical compositions comprisingan anthracycline glycoside of the formula (A) or a pharmaceuticallyacceptable salt thereof in combination with a pharmaceuticallyacceptable diluent or carrier. These compositions contain atherapeutically effective amount of the glycoside or its salt. Theinvention additionally provides methods of using the glycosides or theirsalts in treating certain mammalian tumors by administering atherapeutically effective amount to a patient.

The following Examples illustrate the invention. EXAMPLE 1 Preparationof 1-methoxy-2,2'-oxydiacetaldehyde (BI)

A solution of methyl-α-L-arabinopyranoside (1.64 g, 10 mmol) in water(25 ml) was treated in portions with sodium periodate (4.3 g) at 0° C.After 3 hours, the iodate and excess periodate were precipitated byaddition of a solution of barium chloride. The mixture was neutralized(BaCO₃) and filtered, the insoluble material being washed with water. Tothe filtrate ethanol was added and set aside overnight in therefrigerator to precipitate inorganic material. After filtration, thesolution was concentrated to a syrup that was extracted withacetonitrile (10 ml). The extract was used for the next step withoutfurther purification.

EXAMPLE 2 Preparation of3'-deamino-3'-(2"-methoxy-4"-morpholinyl)daunorubicin (I)

To a solution of daunorubicin hydrochloride (0.57 g, 1 mmol) in 40 ml ofacetonitrile-water (1:1) was added the solution of dialdehyde preparedas described in example 1. The pH was adjusted to 7.4 with a solution ofsodium hydrogen carbonate. After 2 hours the stirred mixture was treatedwith a solution of 0.064 (1 mmol) of NaBH₃ CN in 5 ml of water. After 15minutes the mixture was worked up by dilution with water (100 ml) andextraction with methylene chloride. The organic phase was evaporatedunder vacuum. The resulting residue is purified by flash chromatographyon silica gel column using methylene dichloride:acetone (96:5 v/v) asthe eluting system. There are obtained 0.360 g (yield 55%) of I that wasisolated as hydrochloride. m.p. 160°-161° C.

NMR (200 MHz, CDCl₃): 13.98 (s, 1H, OH-6), 13.28 (s, 1H, OH-11), 8.02(d, J=8.0 Hz, 1H, H-1), 7.77 (t, J=8.0 Hz, 1H, H-2), 7.38 (d, J=8.0 Hz,1H, H-3), 5.54 (m, 1H, H-1'), 5.26 (dd, J=2.2, 4.2 Hz, 1H, H-7), 4.64(s, 1H, OH-9), 4.49 (dd, J=2.6, 4.0 Hz, ##STR5## 4.07 (s, 3H, OCH₃ -4),4.01 (dq, J=1.0, 6.5 Hz, 1H, H-5'), 3.90 (m, 1H, NH₂ -CH(H)O), 3.65 (m,1H, H-4'), 3.4-3.6 (m, 1H, NCH₂ --CH(H)O), 3.38 (s, 3H, OCH₃ --CHCH₂ N),3.21 (dd, J=1.8, 19.0 Hz, 1H, H-10e), 2.93 (d, J=19.0 Hz, 1H, H-10ax),2.61 (dd, J=4.0, 11.4 Hz, NCH_(e) (H)--CHOCH₃), 2.3-2.5 (m, 3H, H-8e,H-3', NCH_(ax) (H)--CHOCH₃), 2.40 (s, 3H, CH₃ -14), 2.08 (dd, J=4.2,15.0 Hz, 1H, H-8ax), 1.7-1.8 (m, 2H, CH₂ -2' ), 1.36 (d, J=6.5 Hz, 3H,CH₃ -5').

EXAMPLE 3 Preparation of3'-deamino-3'-(2"-methoxy-4"-morpholinyl)-doxorubicin (II)

The synthesis of the compound II starting from doxorubicin hydrochloride(0.58 g, 1 mmol) and the 1-methoxy-2,2-oxybisacetaldehyde solution ofExample 1 was performed according to the procedure described in Example2. 3'-Deamino-3'-(2"-methoxy-4"-morpholinyl)doxorubicin (II) wasobtained as the hydrochloride in an amount of 0.38 g (yield 55%) m.p.163°-164° C.

NMR (200 MHz, CDCl₃): 13.97 (s, 1H, OH-6), 13.26 (s, 1H, OH-11), 8.03(dd, J=1.2, 8.0 Hz, 1H, H-1), 7.78 (t, J=8.0 Hz, 1H, H-2), 7.40 (dd,J=1.2, 8.0 Hz, 1H, H-3), 5.55 (, J=2.6 Hz, 1H, H-1'), 5.29 (dd, J=2.2,3.9 Hz, 1H, H-7), 4.74 (d, J=3.0 Hz, 2H, CH₂ OH-14), 4.49 (dd, J=2.5,4.0 Hz, ##STR6## 4.08 (s, 3H, OCH₃ -4), 3.93 (dq, J=6.5, 1.0 H, 1H,H-5'), 3.92 (m, 1H, NCH₂ CH(H)O), 3.67 (dd, J=2.0, 1.0 Hz, 1H, H-4'),3.54 (m, 1H, NCH₂ CH(H)O), 3.38 (s, 3H, NCH₂ --CH--OCH₃), 3.26 (dd,J=1.7, 19.0 Hz, 1H, H-10e), 3.00 (d, J=19.0 Hz, 1H, H-10ax), 2.60 (dd,J=4.0, 11.4 Hz, 1H, ##STR7## 2.47 (m, 2H, NCH₂ CH₂ O), 2.45 (m, 1H,##STR8## 2.3-2.4 (m, 1H, H-8e), 2.34 (m, 1H, H-3'), 2.14 (dd, J=3.9,15.0 Hz, H-8ax), 1.76 (m, 2H, CH₂ -2'), 1.36 (d, J=6.5 Hz, 3H, CH₃ -5').

EXAMPLE 4 Preparation of 1-methyl-1'-methoxy-2,2'-oxydiacetaldehyde(BII)

A solution of methyl-α-L-rhamnopyranoside (1.78 g, 10 mmol) in water (25ml) was treated with sodium periodate (4.3 g) at 0° C. After 3 hourssodium hydrogen carbonate was cautiously added to neutralize the acid,the mixture was poured into ethanol (100 ml) and the insoluble materialwas filtered. The filtrate was concentrated to a syrup that wasextracted with acetonitrile (15 ml). The extract was used for the nextstep without further purification.

EXAMPLE 5 Preparation of3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)-daunorubicin (III)

The synthesis of the compound III starting from daunorubicinhydrochloride (0.57 g, 1 mmol) and the1-methyl-1'-methoxy-2,2'-oxydiacetaldehyde solution of Example 4 wasperformed according to the procedure described in Example 2.3'-Deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)daunorubicin wasisolated as the hydrochloride in an amount of 0.34 g (yield 50%) m.p.152° C.

NMR (200 MHz, CDCl₃): 13.97 (s, 1H, OH-6), 13.29 (s, 1H, OH-11), 8.02(dd, J=1.2, 8.0 Hz, 1H, H-1), 7.77 (t, J=8.0 Hz, 1H, H-2), 7.39 (dd,J=1.2, 8.0 Hz, 1H, H-3), 5.53 (m, 1H, H-1'), 5.26 (dd, J=2.0, 4.0 Hz,1H, H-7), 4.67 (s, 1H, OH-9), 4.59 (bd, J=2.0 Hz, 1H, ##STR9## 4.08 (s,3H, OCH₃ -4), 3.9-4.0 (m, 1H, ##STR10## 4.00 (dq, J=1.5, 6.6 Hz, 1H,H-5'), 3.71 (m, 1H, H-4'), 3.34 (s, 3H, ##STR11## 3.21 (dd, J=2.0, 19.2Hz, H-10_(e)) 2.93 (d, J=19.2 Hz, 1H, H-10_(ax)), 2.95 (bd, J=11.0 Hz,1H, ##STR12## 2.83 (bd, J=11.5 Hz, 1H, ##STR13## 2.40 (s, 3H, CH₃ -14),2.35 (ddd, J=2.0, 2.0, 15.0 Hz, 1H, H-8_(e)), 2.17 (dd, J=2.8, 11.5 Hz,1H, ##STR14## 2.07 (dd, J=4.0, 15.0 Hz, 1H, H-8_(ax)), 1.82 (dd, J=11.0,11.0 Hz, 1H, ##STR15## 1.7-1.8 (m, 2H, CH₂ -2'), 1.36 (d, J=6.6 Hz, 3H,CH₃ -5'), 1.09 (d, J=6.2 Hz, 3H, ##STR16##

EXAMPLE 6 Preparation of3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)doxorubicin (IV)

The synthesis of the compound (IV) starting from doxorubicinhydrochloride (0.56 g, 1 mmol) and the1-methyl-1'-methoxy-2,2'-oxydiacetaldehyde solution of Example 4 wasperformed according to the procedure described in Example 2.3'-Deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)-doxorubicin (IV) wasisolated as the hydrochloride in an amount of 0.35 g (yield 51%) m.p.162° C.

NMR (200 MHz, CDCl₃): 13.88 (s, 1H, OH-6), 13.15 (s, 1H, OH-1'), 7.97(dd, J=1.0, 8.0 Hz, 1H, H-1), 7.76 (t, J=8.0 Hz, 1H, H-2), 7.37 (dd,J=1.0, 8.0 Hz, 1H, H-3), 5.53 (m, 1H, H-1'), 5.30 (dd, J=2.1, 4.0 Hz,1H, H-7), 4.74 (s, 2H, CH₂ OH-14), 4.60 (bd, J=2.3 Hz, 1H, ##STR17##4.08 (s, 3H, OCH₃ -4), 4.00 (m, 1H, ##STR18## 3.92 (dq, J=1.0, 6.5 Hz,1H, H-5'), 3.71 (m, 1H, H-4'), 3.34 (s, 3H, ##STR19## 3.27 (dd, J=1.5,19.0 Hz, 1H, H-10_(e)), 3.03 (d, J=19.0 Hz, 1H, H-10_(ax)), 2.97 (bd,J=11.5 Hz, 1H, ##STR20## 2.82 (bd, J=11.5 Hz, 1H, ##STR21## 2.1-2.4 (m,4H, CH₂ -8, H-3, ##STR22## 1.83 (dd, J=11.5, 11.5 Hz, 1H, ##STR23## 1.75(m, 2H, CH₂ -2'), 1.36 (d, J=6.5 Hz, 3H, CH₃ -5'), 1.10 (d, J=6.5 Hz,3H, ##STR24##

EXAMPLE 7 Preparation of1-hydroxymethyl-1'-methoxy-2,2'-oxydiacetaldehyde (BIII)

A solution of methyl-α-D-glucopyranoside (1.95 g, 10 mmol) in 20 ml ofwater was treated in portions with sodium periodate (4.3 g) at 0° C. Aolution of the 1-hydroxymethyl-1'-methoxy-2,2'-oxydiacetaldehydethus-prepared was obtained by the procedure described in Example 1.

EXAMPLE 8 Preparation of3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-daunorubicin(V)

The synthesis of the compound (V) starting from daunorubicinhydrochloride (0.57 g, 1 mmol) and the1-hydroxymethyl-1'-methyl-2,2'-oxydiacetaldehyde solution of Example 7was performed according to the procedure described in Example 2.3'-Deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-daunorubicin(V) was isolated as the hydrochloride in an amount of 0.35 g (yield 50%)m.p. 164° C.

NMR (200 MHz, CDCl₃): 13.98 (s, 1H, OH-6), 13.28 (s, 1H, OH-11), 8.02(dd, J=1.0, 8.0 Hz, 1H, H-1), 7.78 (t, J=8.0 Hz, 1H, H-2), 7.38 (dd,J=1.0, 8.0 Hz, 1H, H-3), 5.54 (m, 1H, H-1'), 5.28 (dd, J=2.0, 4.0 Hz,1H, H-7), 4.66 (bs, 1H, ##STR25## 4.63 (s, 1H, OH-9), 4.08 (s, 3H, OCH₃-4), 4.02 (dq, J=2.0, 6.5 Hz, 1H, H-5'), 3.95-4.05 (m, 1H, ##STR26##3.67 (m, 1H, H-4'), 3.65 (dd, J=3.0, 12.0 Hz, 1H, ##STR27## 3.55 (dd,J=5.0 12.0 Hz, 1H, ##STR28## 3.34 (s, 3H, ##STR29## 3.33 (dd, J=1.0,19.0 Hz, 1H, H-10_(e)), 3.08 (bd, J=11.0 Hz, 1H, ##STR30## 2.95 (d,J=19.0 Hz, 1H, H-10ax), 2.75 (bd, J=11.0 Hz, 1H, ##STR31## 2.40 (s, 3H,CH₃ -1H), 2.3-2.45 (m, 2H, H-3', H-8_(e)), 2.17 (dd, J=4.0, 13.0 Hz, 1H,H-8_(ax)), 2.15 (m, 1H, ##STR32## 2.07 (dd, J=11.0, 11.0 Hz, 1H,##STR33## 1.79 (m, 2H, CH₂ -2'), 1.36 (d, J=6.5 Hz, 3H, CH₃ -5').

EXAMPLE 9 Preparation of3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-doxorubicin(VI)

The synthesis of the compound VI starting from doxorubicin hydrochloride(0.58 g, 1 mmol) and the1-hydroxymethyl-1'-methyl-2,2'-oxydiacetaldehyde solution of Example 7was performed according to the procedure described in Example 2.3'-Deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-doxorubicin(VI) was isolated as hydrochloride in an amount of 0.36 g (yield 51-52%)m.p. 165° C.

NMR (200 MHz, CDCl₃): 13.92 (s, 1H, OH-6), 13.17 (s, 1H, OH-11), 7.99(d, J=8.0 Hz, 1H, H-1), 7.76 (t, J=8.0 Hz, 1H, H-2), 7.38 (d, J=8.0 Hz,1H, H-3), 5.52 (m, 1H, H-1'), 5.25 (m, 1H, H-7), 4.73 (s, 2H, CH₂OH-14), 4.70 (s, 1H, OH-9), 4.66 (bs, 1H, ##STR34## 4.06 (s, 3H, OCH₃-4), 3.9-4.0 (m, 1H, ##STR35## 3.92 (dq, J=2.0, 6.5 Hz, 1H, H-5'), 3.68(m, 1H, H-4'), 3.61 (dd, J=4.0, 11.5 Hz, 1H, ##STR36## 3.51 (dd, J=5.5,11.5 Hz, 1H, ##STR37## 3.33 (s, 3H, NCH₂ CH-OCH₃), 3.20 (dd, J=1.0, 19.0Hz, 1H, H-10_(e)), 3.00 (bd, J=11.0 Hz, 1H, ##STR38## 2.93 (d, J=19.0Hz, 1H, H-10_(ax)), 2.73 (bd, J=11.0 Hz, 1H, ##STR39## 2.3-2.5 (m, 2H,H-3', H-8_(e)), 2.20 (dd, J=4.0, 13.0 Hz, 1H, H-8_(ax)), 2.15 (dd,J=3.0, 11.0 Hz, 1H, ##STR40## 2.04 (dd, J=11.0, 11.0 Hz, 1H, ##STR41##1.80 (m, 2H, CH₂ -2'), 1.35 (d, J=6.5 Hz, 3H, CH₃ -5').

BIOLOGICAL ACTIVITY OF I-VI

The compounds have been tested in several experimental systems in orderto ascertain their cytotoxicity and antitumor activity in experimentalanimals. Data reported in Table I show that all the compounds are morecytotoxic than the parent drugs daunorubicin and doxorubicin.

The primary screening in vivo was carried out in CDF-1 mice bearing P388ascetic leukemia (10⁶ cells/mouse). Results are reported in Table II.All the compounds are active, in particular compound V is more activethan daunorubicin giving at the same optimal dose a higher increase ofthe mice life span. The doxorubicin analogs II, IV and VI are morepotent than the parent drug. In particular II is 60 times more potentand exhibits a major efficacy (T/C % 295). The doxorubicin analogs II,IV, VI have been tested in C3H mice bearing the Gross leukemia injectediv (2×10⁶ cell/mouse). Data are reported in Table III. Administered ivon day 1 after the tumor inoculation, the compounds were more potentthan doxorubicin. Compound II has been studied on P388 leukemia cellsresistant to doxorubicin (P388/DX) in vitro and in vivo. Cytotoxicitytests were carried out exposing the cells to various drug concentrationsfor 48 hrs. At the end of exposure period cells were counted with acoulter cell counter, and the ID₅₀ (dose which gives 50% reduction ofthe cell number in comparison with untreated controls) was calculated.Results reported in Table IV show that II was 40 times more cytotoxicthan doxorubicin on P388 leukemia cells and was very active also onP388/DX leukemia cells while doxorubicin on this line is obviouslyinactive. Compound II has been tested also in vivo in BDF-1 mice bearingP388/DX leukemia. The data reported in Table V show that the compound at0.15 mg/Kg is very active (T/C % 165).

                  TABLE I    ______________________________________    Colony inhibition test against HeLa cells    in vitro (treatment for 24 hrs)    COMPOUND         ID.sub.50 (ng/ml)    ______________________________________    DAUNORUBICIN     18.6    I                2.0    III              1.8    V                10.5    DOXORUBICIN      18    II               0.96    IV               0.32    VI               9.0    ______________________________________

                  TABLE II    ______________________________________    Antitumor activity against P388 leukemia    treatment ip on day 1             Dose                     Toxic    Compound (mg/Kg)  T/C %.sup.a                                LTS.sup.b                                      deaths.sup.c    ______________________________________    DAUNORU- 2.9      145       0/10  0/10    BICIN    4.4      150       0/10  1/10    I        0.13     136       0/10  0/10    V        2.0      145       0/10  0/10             3.0      164       0/10  0/10    DOXORU-  6.6      214       0/10  0/10    BICIN    10       214       1/10  0/10    II       0.15     295       2/10  0/10    IV       0.2      173       0/10  0/10    VI       1.33     164       0/10  0/10             2        195       0/10  0/10    ______________________________________     .sup.a Median survival time; % over untreated controls     .sup.b Long term survivors (>60 days)     .sup.c Evaluated on the basis of autopsy findings on dead mice

                  TABLE III    ______________________________________    Activity on Gross leukemia (IV-1)               Dose                       Toxic    Compound   (mg/Kg)   T/C %.sup.a                                   LTS.sup.b                                          deaths.sup.c    ______________________________________    DOXORUBICIN               10        183       0/10   0/10               13        200       0/10   0/10    II         0.16      150       0/10   0/10    IV         0.27      142       0/10   0/10    VI         2         150       0/10   0/10    ______________________________________     .sup.a,b,c, see Table II

                  TABLE IV    ______________________________________    Effect on sensitive and doxorubicin-resistant    P388 Leukemia in vitro                  ID.sub.50 (ng/ml).sup.a    Compound        P388.sup.b                            P388/DX.sup.c    ______________________________________    Doxorubicin     12      1500    II              0.3       3    ______________________________________     .sup.a Dose giving 50% reduction of cell number in comparison with     untreated controls     .sup.b P388 leukemia cells sensitive to doxorubicin     .sup.c P388 leukemia cells resistant to doxorubicin

                  TABLE V    ______________________________________    Effect on doxorubicin-resistant P388 leukemia    in vivo              dose                       Toxic.sup.c    Compound  (mg/Kg)   T/C.sup.a LTC.sup.b                                         deaths    ______________________________________    Doxorubicin              4.4       110       0/10   0/10              6.6       100       0/10   0/10    II        0.075     100       0/10   0/10              0.15      165       0/10   1/10    ______________________________________     .sup.a,b,c, see Table II

We claim:
 1. An anthracycline glycoside of the formula A: ##STR42##wherein X is hydrogen or hydroxy and R is hydrogen or a methyl or ahydroxymethyl group; or pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1, which is3'-deamino-3'-(2"-methoxy-4"-morpholinyl)-daunorubicin or itshydrochloride salt.
 3. A compound according to claim 1, which is3'-deamino-3'-(2"-methoxy-4"-morpholinyl)doxorubicin or itshydrochloride salt.
 4. A compound according to claim 1, which is3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)-daunorubicin or itshydrochloride salt.
 5. A compound according to claim 1, which is3'-deamino-3'-(2"-methoxy-6"-methyl-4"-morpholinyl)-doxorubicin or itshydrochloride salt.
 6. A compound according to claim 1, which is3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-daunorubicinor its hydrochloride salt.
 7. A compound according to claim 1, which is3'-deamino-3'-(2"-methoxy-6"-hydroxymethyl-4"-morpholinyl)-doxorubicinor its hydrochloride salt.
 8. A pharmaceutical composition comprising aneffective amount of an anthracycline glycoside or a pharmaceuticallyacceptable salt thereof as claimed in any one of claims 1 to 7 inadmixture with a pharmaceutically acceptable diluent or carrier, fortreatment of P388 leukemia or Gross leukemia.
 9. A method of treatingP388 leukemia or Gross leukemia in a subject in need of such treatment,which comprises administering to the subject an effective amount of ananthracycline glycoside or a pharmaceutically acceptable salt thereof asclaimed in any one of claims 1 to 7.